Intragenic antagonistic roles of protein and circRNA in tumorigenesis
Intragenic antagonistic roles of protein and circRNA in tumorigenesis
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DOI：
10.1038/s41422-019-0192-1
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发表时间：
2019-08-01
期刊：
影响因子：
44.1
通讯作者：
Pandolfi, Pier Paolo
中科院分区：
文献类型：
--
作者：
Guarnerio, Jlenia;Zhang, Yang;Pandolfi, Pier Paolo
circrna产生于mRNA加工过程中的反向剪接事件，当不受调控时，它可以在癌症中发挥积极作用。在这里，我们描述了一种由Zbtb7a基因（也称为POKEMON， LRF）在间充质肿瘤进展背景下编码的新circRNA （circPOK）。circPOK作为一种非编码的原致癌RNA，独立于其线性转录对应物，并通过编码Pokemon转录因子作为肿瘤抑制因子。我们发现circPOK通过共同激活ILF2/3复合物来调节促增殖因子和促血管生成因子。重要的是，Pokemon蛋白和circRNA的表达在癌症中通过不同的转录后调控异常解耦。因此，我们确定了一种新型的遗传单位，iRegulon，它产生生物化学上独特的RNA产物，圆形和线性，具有多种和相反的功能。我们的发现进一步扩展了控制正常生物输出的细胞库，而这些成分的异常表达可能是包括癌症在内的疾病发病机制的基础。
circRNAs arise from back splicing events during mRNA processing, and when deregulated can play an active role in cancer. Here we characterize a new circRNA (circPOK) encoded by the Zbtb7a gene (also kown as POKEMON, LRF) in the context of mesenchymal tumor progression. circPOK functions as a non-coding proto-oncogenic RNA independently and antithetically to its linear transcript counterpart, which acts as a tumor suppressor by encoding the Pokemon transcription factor. We find that circPOK regulates pro-proliferative and pro-angiogenic factors by co-activation of the ILF2/3 complex. Importantly, the expression of Pokemon protein and circRNA is aberrantly uncoupled in cancer through differential post-transcriptional regulation. Thus, we identify a novel type of genetic unit, the iRegulon, that yields biochemically distinct RNA products, circular and linear, with diverse and antithetical functions. Our findings further expand the cellular repertoire towards the control of normal biological outputs, while aberrant expression of such components may underlie disease pathogenesis including cancer.